Natural prostaglandins are alicyclic compounds related to prostanoic acid, the structure of which is: ##STR2## By convention, the carbon atoms of prostanoic acid are numbered sequentially from the carboxylic carbon atom. An important stereo-chemical feature of this compound is the trans-orientation of the C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20 sidechains, which orientation is common to all natural prostaglandins. In prostanoic acid, as elsewhere in this specification, solid lines (--) provide a reference plane (such as the cyclopentyl ring or the bonds between atoms C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20 ; a dashed line ( - - - ) indicates projection of a covalent bond below the reference plane (alpha-configuration); while a wedged line ( ) represents orientation above the reference plane (beta-configuration). In some structures, however, a swung dash or serpentine line ( ) denotes orientation of a covalent bond either above or below the plane of reference (indicated by the Greek letter xi in the nomenclature of such structure).
Natural prostaglandins have the general structure, ##STR3## in which L and M may be ethylene or cis-vinylene radicals. When the cyclopentyl ring is substituted with a carbonyl group at the 9 position and an alpha hydroxyl group at the 11 position, i.e., ##STR4## an important type of prostaglandin known as the E-class is depicted.
The above formula for natural prostaglandins and the representation of the cyclopentyl moiety depict the net-isomer, i.e., the C.sub.7 -C.sub.8 bond in the alpha configuration and the C.sub.12 -C.sub.13 bond in the beta-configuration. In the ent-isomer (which does not occur in nature), the direction of the bonds at C.sub.7 -C.sub.8 and C.sub.12 -C.sub.13 is reversed.
When L and M in the foregoing formula are ethylene (as opposed to cis-vinylene) there is only a trans-double bond at the (C.sub.13 -C.sub.14 position and such a prostaglandin is known as type 1. Then there is a carbonyl moiety at C.sub.9 and an alpha-hydroxyl moiety at C.sub.11 with a trans-double bond at C.sub.13 -C.sub.14, i.e., ##STR5## the prostaglandin is known as PGE.sub.1 or 11.alpha., 15S-dihydroxy-9-oxoprost-13E-en-1-oic acid.
Naturally occurring PGE.sub.1 or synthetic analogues thereof elicit biochemical and physiological effects in a variety of mammalian systems. For example, in rats PGE.sub.1 increases the release of growth hormone while in sheep it inhibits ovarian progesterone secretion. In mice, PGE.sub.1 increases thyroid activity whereas in hypophysectomized rats it stimulates stereoidogenesis in the adrenal glands. In general PGE compounds relax in vitro human uterine muscle strips, and PGE.sub.1 has been found to inhibit gastric secretion.
It has been found that PGE compounds may, in the respiratory area, prove beneficial in the therapy of bronchial asthma and other diseases involving bronchoconstriction due to their bronchodilatory effect. In this regard carbinol analogues of PGE.sub.1, i.e., those in which the --COOH group at the 1-position is converted to a --CH.sub.2 OH group, have shown great potential as antiasthma agents. For example, U.S. Pat. No. 4,022,912 issued on May 10, 1977 discloses that 1, 11.alpha., 15S-trihydroxyprost-13E-en-9-one of the formula: ##STR6## is an excellent bronchodilator which is much more effective in this regard than naturally occurring PGE.sub.1.
Carbinol derivatives of PGE.sub.1 also possess great potential as anti-ulcer agents due to their demonstrated activity in inhibiting gastric secretion in an individual for whom such therapy is indicated. Thus, 1,11,15-trihydroxy-16,20-methano analogues of PGE.sub.1, having the general structural formula: ##STR7## wherein m is an integer of from 2 to 4, and A is an ethylene or vinylene radical are useful in this regard. These compounds are prepared by reacting an organolithiocuprate of the formula: ##STR8## in which Lig is tri-(di-alkylamino)phosphine of 6-12 carbon atoms, trialkylphosphine having 3-12 carbon atoms, diarylphosphine, dialkylsulfide having 2-8 carbon atoms, arylsulfide, or di-(trialkylsilyl)amino having 6-12 carbon atoms; R.sup.t is a radical having the formula: ##STR9## wherein and subsequently elsewhere E is tetrahydropyran-2-yl, trialkylsilyl having 3 to 12 carbon atoms, triarylsilyl, alkoxy-alkyl having 2-6 carbon atoms, or triarylmethyl; R.sup.r is iodide, thiophenylate, alkyn-1-yl having 3 to 8 carbon atoms, or R.sup.t ; and x is an integer of the set 0-4 provided that x is 0 only when R.sup.r is thiophenylate; with a 2-(.omega.-hydroxyalkyl)-4R,4S or 4RS-hydroxycyclopent-2-enone of the formula: ##STR10## to obtain a carbinol analogue of PGE.sub.1 having the formula: ##STR11## which can subsequently be hydrogenated to yield the carbinol analogue of PGE in which A is ethylene, i.e., ##STR12##
The substituted cyclopent-2-en-1-one set out in formula VIII is an essential intermediate in the formation of the carbinol analogues of formulae IV, IX and X.
Typically the substituted cyclopent-2-en-1-one set out in formula VIII (in which the ring hydroxyl has the R configuration) is prepared from ethyl 9-oxodecanoate as described in Tetrahedron Letters, 2063 (1977). Thus, ethyl 9-oxodecanoate is converted in four steps as described to the intermediate substituted cyclopentan-1,3,4-trione of the formula: ##STR13## wherein m is 3; and then intermediate XI is treated with an aqueous culture of an appropriate microorganism such as Dipodascas uninucleatus as disclosed in U.S. Pat. No. 3,773,622 to yield after exhaustive extraction of the beer, a very polar product of the formula: ##STR14## which is usually contaminated with other fermentation products and must therefore be purified by chromatography. The purified XI-A is then converted in three steps to an intermediate of structure VIII.
According to a process described in J. Amer. Chem. Soc., 95, 1676 (1973) alkyl 9-oxodecanoate is converted in one step to a product of the formula: ##STR15## wherein m is 3 and R.sub.1 is an alkyl group containing from 1 to 4 carbon atoms; and then intermediate XI according to U.S. Pat. No. 3,773,622 is converted by contact with appropriate microorganisms to a product of the formula: ##STR16## wherein m and R.sub.1 are as defined above, in good yields without chromatography.
The S compound represented by the formula: ##STR17## is prepared as described in J. Amer. Chem. Soc., 97, 865 (1975) and the RS material, i.e., ##STR18## is prepared as described in Ann. N.Y. Acad. Sci., 180, 64 (1971).